Parkinson's disease (PD) is the most common degenerative hypokinetic movement disorder. Great strides have been made in the understanding of the pathophysiological mechanisms underlying the neurodegenerative processes in PD, prompting clinical trials of new therapies aimed at slowing or halting the progression of these diseases. To assess these new therapies, reliable in vivo markers of neuronal loss are needed. Currently available clinical measures of disease progression are relatively insensitive, and may not accurately reflect the extent of neuropathological change. Alternatively, quantitative biologically relevant brain imaging markers now exist which may be suitable as outcome measures for clinical trials. Specifically, we have developed three novel methods of assessing disease progression using positron emission tomography (PET): (1) The quantification of dopaminergic function using a radioligand which binds selectively to the dopamine transporter (DAT); (2) The quantitation of dynamic changes in brain-behavior relationships using regional blood flow activation and network analysis. The goal of the proposed project is to assess the extent to which neurochemical and functional PET imaging markers are sensitive to change in early stage PD, and to compare these measures to standard clinical induces of disease progression. To this end, we propose to extend our baseline functional imaging studies in early stage patients by carrying out longitudinal PET determinations of the neurochemical, metabolic, and functional activation markers over a three-year study. These studies will allow us to trace the temporal evolution of these imaging indices and to assess their relationship to standardized clinical measures of disease severity. We hypothesize that PET measures will be more sensitive to disease progression that clinical measures. If this is the case, clinical trials designed to assess potential neuroprotective therapies could require fewer patients and be completed in less time.